Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Eurofins Ntd Llc |
RCV000324567 | SCV000338445 | uncertain significance | not provided | 2016-01-04 | criteria provided, single submitter | clinical testing | |
Counsyl | RCV000673996 | SCV000799264 | uncertain significance | Autosomal recessive limb-girdle muscular dystrophy type 2I | 2018-04-06 | criteria provided, single submitter | clinical testing | |
Invitae | RCV001859617 | SCV002308265 | likely pathogenic | Walker-Warburg congenital muscular dystrophy | 2023-09-25 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 182 of the FKRP protein (p.Tyr182His). This variant is present in population databases (rs753390261, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of limb-girdle muscular dystrophy (PMID: 28688748, 30060766). ClinVar contains an entry for this variant (Variation ID: 285433). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FKRP protein function. This variant disrupts the p.Tyr182Cys amino acid residue in FKRP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14647208, 27439679, 28931339, 30003095). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
Ambry Genetics | RCV002348000 | SCV002652290 | likely pathogenic | Cardiovascular phenotype | 2021-12-13 | criteria provided, single submitter | clinical testing | The p.Y182H variant (also known as c.544T>C), located in coding exon 1 of the FKRP gene, results from a T to C substitution at nucleotide position 544. The tyrosine at codon 182 is replaced by histidine, an amino acid with similar properties. This variant has been identified in patients with limb-girdle muscular dystrophy (LGMD) in both the homozygous and compound heterozygous states (Sframeli M et al. Neuromuscul Disord, 2017 Sep;27:793-803; Johnson K et al. Skelet Muscle, 2018 07;8:23). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |